At the transcriptional level, little is known about the pathways that are associated with the active maintenance of T cell quiescence. We recently showed that cell-intrinsic signaling pathways are required to maintain mature T cells in a quiescent state; if these pathways are disrupted, resting T cells become aberrantly activated even in lympho-replete hosts in the absence of antigen challenge (Nat Immunol 2011). Our long-term goals are to identify such regulatory genes and pathways that actively restrain T cel activation, and to define their roles in T cell quiescence, T cell homeostasis, and in primary and memory T cell responses. In the immediate future, specifically, we are asking how the pathways associated with T cell quiescence impact the rate and extent of T cell activation, thereby affecting the kinetics and magnitude of the response and effector and memory T cell differentiation. We will also address a long-recognized but poorly understood process that is fundamental to the maintenance of memory T cells: is enforcing memory T cell quiescence an essential mechanism for long-term memory survival? The studies will provide fundamental information and new mechanistic insights to guide therapeutic manipulation of T cell quiescence versus activation in a broad range of clinical settings including autoimmunity, infectious diseases, and vaccine development. Recently we have identified Foxp1 as an essential transcription regulator for maintaining the quiescence of naive T cells during homeostasis. In this proposal, we will determine the role of Foxp1 proteins in the antigen-induced T cell response and elucidate the mechanisms whereby Foxp1 enforces quiescence. The two specific aims are: 1) Determine the regulation of Foxp1 on T cel activation and memory. We have generated several Foxp1 isoform-specific conditional transgenic mice as well as a Foxp1 inducible deletion mouse model. We will utilize these novel gain- and loss-of-function mouse lines to elucidate the role of Foxp1 and its isoforms in T cel activation and memory. 2) Elucidate the molecular mechanisms by which Foxp1 enforces T cell quiescence. Recently we have established a genome-wide Foxp1 ChIP-sequencing assay and identified a number of novel Foxp1-candidate target genes. We will combine both candidate and unbiased genome-wide approaches to elucidate how the Foxp1 pathway negatively regulates cell growth/metabolism and cell cycle progression, thereby enforcing T cell quiescence. Based on the unique mouse lines and model systems that we have established and the unique insights of Foxp1 targets, our study is highly significant as it has the potential to reveal several novel and important molecular mechanisms underlying the transcriptional network of Foxp1 in regulating T cell quiescence, activation and memory. PUBLIC HEALTH RELEVANCE: Public Health Relevance Statement Recent studies have shown that T cell quiescence is not by default but actively maintained by both cell extrinsic and intrinsic mechanisms, about which little is known at the molecular level. The research on understanding the transcriptional regulation of T cell quiescence by key factors will provide fundamental information for devising strategies to manipulate T cell quiescence and activation in a wide range of clinical settings including autoimmunity, infectious diseases, and vaccine development.